Primary biliary cirrhosis (PBC) is a disease of unknown etiology characterized by inflammation and necrosis of intrahepatic bile ducts, and associated features suggesting the occurrence of systemic autoimmunity. Several aspects of lymphocyte function have been investigated in patients with PBC. Previous work demonstrated that patients with PBC have diminished suppression of pokeweed mitogen stimulated immunoglobulin synthesis in vitro, and a diminished proliferative response in the autologous MLR, which in normal individuals may represent an activation pathway for suppressor cells. In current studies, patients with PBC were found to have diminished T cell mediated suppression of immunoglobulin synthesis by Epstein Barr virus stimulated autologous B cells. In addition, patients with PBC were found to have diminished T cell mediated suppression of immunoglobulin synthesis by Epstein Barr virus stimulated autologous B cells. In addition, patients with PBC had increased numbers of B cells in peripheral blood which spontaneously secrete immunoglobulin. These findings demonstrate that patients with PBC have abnormality of immunoregulatory function which may involve both T and B cells. In other studies, the diminished natural killer (NK) cell function of patients with PBC was studied. The number of effector cells, as determined by reactivity with the monoclonal antibody HNK-1, and the subpopulation of NK cells lacking T cell markers, was found to be normal. No evidence for suppression of NK activity by lymphocytes or serum factors could be found in PBC. Interferon and interleukin-2 were found to only partially reconstitute the NK defect. Abnormal function of immunoregulatory circuits and cytotoxic cells may contribute to the pathogenesis of autoimmunity in diseases such as PBC. Further investigations will concentrate on details of the cellular mechanisms which may be the basis for these defects in PBC.